RESUMO
Systemic medications categorized as diphenylhydantoin, calcineurin inhibitor and calcium channel blocker may have effects on the oral cavity by modifying the inflammatory and immune response and causing undesired tissue proliferative reactions. Calcineurin inhibitors are medications commonly used for long periods in patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) and solid organ transplantation. Medication-related fibrovascular hyperplasia (MRFH) is an extra gingival hyperplastic nodular growth associated with medications use. This study reports five cases of pediatric patients (6 to 12-years-old) diagnosed with Fanconi anemia (FA) after HSCT who presented similar oral mucosal lesions associated with the use of cyclosporine, phenobarbital and amlodipine. After excision of the lesions, histopathological analysis described them as pyogenic granuloma (PG). As the aetiology of the lesions manifested by the patients was associated with the use of medications, the final diagnosis was MRFH. Despite the clinical and histopathological similarity between PG and MRFH, it is fundamental to know the aetiological agent for achieving definitive diagnosis and correct management. Considering the etiologic agent (medication) and histopathological findings, it is suggested that the most appropriate term for this manifestation should be "medication-related fibrovascular hyperplasia". The correct nomenclature related to extra gingival hyperplastic lesions identified in patients on medications with potential to induce hyperplastic reactions should be adopted to facilitate scientific communication and improve the treatment.
Assuntos
Bloqueadores dos Canais de Cálcio/efeitos adversos , Anemia de Fanconi/terapia , Granuloma Piogênico/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/efeitos adversos , Doenças da Boca/induzido quimicamente , Anlodipino/efeitos adversos , Criança , Ciclosporina/efeitos adversos , Feminino , Humanos , Hiperplasia/induzido quimicamente , Masculino , Fenobarbital/efeitos adversosRESUMO
OBJECTIVE: The objective of this study is to report the case of a patient who underwent hematopoietic stem cell transplantation for Hodgkin's lymphoma treatment and developed multiple tongue lesions during recovery. METHODS AND RESULTS: This is the case report of a patient who developed ulcerated lesions with areas of depapillation on the border and dorsum of the tongue. The ulcer evolved to a reddish fibrous hyperplastic nodule, similar to adjacent mucosa. The patient was using a series of medications, such as antifungals, antibiotics, antivirals, corticosteroids, and analgesics in addition to immunosuppression with cyclosporine. Considering the medical history of the patient, a biopsy was performed. Histopathological analyses describe hyperplasia, granulation tissue, vascular proliferation, and intense inflammatory infiltrate, and the diagnosis was of medication-related fibrovascular hyperplasia (MRFH). CONCLUSION: Patients in use of cyclosporine are at risk to develop oral lesions, such as MRFH. The correct diagnosis is important, so the adequate treatment and follow-up are instituted even considering the immunosuppression protocol.
Assuntos
Úlceras Orais , Doenças da Língua , Biópsia , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Úlceras Orais/patologia , Língua , Doenças da Língua/induzido quimicamente , Doenças da Língua/diagnóstico , Doenças da Língua/patologiaRESUMO
The aim of the study was to evaluate the time course of the effects of urban air pollutants on the ocular surface, focusing on the morphological changes, the redox balance, and the inflammatory response of the cornea. 8-week-old mice were exposed to urban or filtered air (UA-group and FA-group, respectively) in exposure chambers for 1, 2, 4, and 12â¯weeks. After each time, the eyes were enucleated and the corneas were isolated for biochemical analysis. UA-group corneas exhibited a continuous increase in NADPH oxidase-4 levels throughout the exposure time, suggesting an increased production of reactive oxygen species (ROS). After 1â¯week, an early adaptive response to ROS was observed as an increase in antioxidant enzymes. After 4â¯weeks, the enzymatic antioxidants were decreased, meanwhile an increase of the glutathione was shown, as a later compensatory antioxidant response. However, redox imbalance took place, evidenced by the increased oxidized proteins, which persisted up to 12â¯weeks. At this time point, corneal epithelium hyperplasia was also observed. The inflammatory response was modulated by the increase in IL-10 levels after 1â¯week, which early regulates the release of TNF-α and IL-6. These results suggest that air pollution alters the ocular surface, supported by the observed cellular hyperplasia. The redox imbalance and the inflammatory response modulated by IL-10 play a key role in the response triggered by air pollutants on the cornea. Taking into account this time course study, the ocular surface should also be considered as a relevant target of urban air pollutants.
Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Epitélio Corneano/patologia , Animais , Brasil , Cidades , Epitélio Corneano/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Interleucina-10/metabolismo , Masculino , Camundongos , NADPH Oxidase 4/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo , Testes de Toxicidade Subaguda , Testes de Toxicidade SubcrônicaRESUMO
The aim of this study was to measure changes in epithelial thickness in the lingual mucosa of golden hamsters submitted to the topical application of distilled alcoholic beverages. Forty golden hamsters were randomly divided into: Group 1-cachaça 48° GL and Group 2-whisky 40° GL. Alcohol was applied to the right side of the tongue, the left side served as control. Seventy microscopic fields were evaluated. The data were submitted to descriptive statistics, the Wilcoxon test and the Mann-Whitney U test (p < 0.05). In Group 1, there was a significant difference in mean total epithelial thickness between the test side and control side (p = 0.044), with significant reductions in the thickness of the epithelial and corneal layers (p < 0.001 and p = 0.021, respectively). At 13 weeks, statistically significant reductions were found in the thickness of both the corneal and epithelial layers (p = 0.032 and p < 001, respectively). At 20 weeks, a statistically significant reduction was found in only the epithelial layer (p = 0.002). In the whisky group, significant increases were found in the thickness of the corneal and epithelial layers (p = 0.015 and p = 0.012, respectively) at 13 weeks. Cachaça 48° GL promoted epithelial atrophy, whereas whisky 40° GL promoted epithelial hyperplasia. Based on the present findings, different types of distilled alcoholic beverages cause different morphometric and morphological changes in the lingual mucosa. Cachaça caused epithelial atrophy, which may facilitate the penetration of carcinogenic agents, whereas whisky caused epithelial hyperplasia, especially in the basal layer, which suggests the onset of the development of premalignant lesions.
Assuntos
Bebidas Alcoólicas/efeitos adversos , Etanol/farmacologia , Mesocricetus/anatomia & histologia , Mucosa Bucal/anatomia & histologia , Língua/anatomia & histologia , Animais , Cricetinae , Epitélio/anatomia & histologia , Epitélio/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Masculino , Mucosa Bucal/efeitos dos fármacos , Língua/efeitos dos fármacosRESUMO
Trastuzumab is a monoclonal antibody targeted against the Human Epidermal Growth Factor Receptor 2 (HER2) overexpressed in some breast cancer. This targeted therapy significantly improves the prognosis of these cancers. Recently an anti-HER2 antibodydrug conjugate was shaped in order to facilitate the targeted delivery of potent cytotoxic drug to cancer cells and to reduce resistance. This formulation, called trastuzumab emtansine (T-DM1), consists of the monoclonal antibody trastuzumab linked to a cytotoxic drug (a derivative of maytansine) via a chemical linker. Little is known about adverse reactions due to this new formulation. Herein we described the case of a woman suffering from a HER2-positive breast cancer, treated with trastuzumab for 30 months followed by T-DM1 monotherapy. After 12 months of T-DM1 treatment, a nodular regenerative hyperplasia confirmed by liver biopsy occurred. T-DM1 was stopped and medical imagery showed a resolution of the nodular regenerative hyperplasia. Unfortunately, hepatic metastasis progressed. Few cases of nodular regenerative hyperplasia induced by T-DM1 have been described so far. Further studies are needed to explore pathogenesis of nodular regenerative hyperplasia with this new antibody-drug conjugate treatment.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Neoplasias Hepáticas/secundário , Maitansina/análogos & derivados , Receptor ErbB-2/efeitos dos fármacos , Trastuzumab/efeitos adversos , Ado-Trastuzumab Emtansina , Biópsia por Agulha , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Feminino , Seguimentos , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Imuno-Histoquímica , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética/métodos , Maitansina/efeitos adversos , Maitansina/uso terapêutico , Pessoa de Meia-Idade , Terapia de Alvo Molecular/efeitos adversos , Medição de Risco , Trastuzumab/uso terapêutico , Suspensão de TratamentoRESUMO
Our aim was to evaluate whether postnatal exposure to endosulfan (ENDO) modifies mammary gland (MG) development in pre- and post-pubertal male rats. From postnatal day 1 (PND1) to PND7, male rats were injected subcutaneously every 48h with either corn oil (vehicle) or 600µg ENDO/kg.bw. On PND21 and PND60, MG and blood samples were collected. Estradiol (E2) and testosterone (T) serum levels, MG histology, collagen fiber organization, proliferation index, and estrogen (ESR1) and androgen receptor (AR) expressions were evaluated. On PND21, E2 and T levels were similar between groups, whereas MG area, perimeter, number of terminal end buds and ESR1 expression were increased in ENDO-exposed rats. These changes were associated with alveolar development and increased organized collagen in the stroma. On PND60, a higher proliferation index in ENDO-exposed rats was correlated with a more developed lobuloalveolar structure. Hyperplastic alveoli and, hyperplastic ducts surrounded by a dense stroma were also observed in this group. T levels and ESR1 expression were similar between groups, whereas E2 levels and AR expression were decreased in ENDO-exposed rats. The exposure to ENDO in the first week of life interferes with the normal development of the MG and induces pre-malignant lesions in post-pubertal male rats.
Assuntos
Endossulfano/toxicidade , Glândulas Mamárias Animais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Endossulfano/sangue , Estradiol/sangue , Hiperplasia/sangue , Hiperplasia/induzido quimicamente , Masculino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Ratos , Ratos Wistar , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Testosterona/sangue , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor ß1 (TGF-ß1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-ß1 and AhR signaling in mouse mammary gland, through AhR+/+ and AhR-/- models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0.05µM HCB induced cell migration and TGF-ß1 signaling, whereas 5µM HCB reduced cell migration, promoted cell cycle arrest and stimulated the dioxin response element (DRE) -dependent pathway. HCB (5µM) enhanced α-smooth muscle actin expression and decreased TGF-ß receptor II mRNA levels in immortalized mouse mammary fibroblasts AhR+/+, resembling the phenotype of transformed cells. Accordingly, their conditioned medium was able to enhance NMuMG cell migration. Assays in C57/Bl6 mice showed HCB (3mg/kg body weight) to enhance ductal hyperplasia, cell proliferation, estrogen receptor α nuclear localization, branch density, and the number of terminal end buds in mammary gland from AhR+/+ mice. Primary culture of mammary epithelial cells from AhR+/+ mice showed reduced AhR mRNA levels after HCB exposure (0.05 and 5µM). Interestingly, AhR-/- mice exhibited an increase in ductal hyperplasia and mammary growth in the absence of HCB treatment, thus revealing the importance of AhR in mammary development. Our findings show that environmental HCB concentrations modulate AhR and TGF-ß1 signaling, which could contribute to altered mammary branching morphogenesis, likely leading to preneoplastic lesions and retaining terminal end buds.
Assuntos
Poluentes Ambientais/toxicidade , Hexaclorobenzeno/toxicidade , Hiperplasia/induzido quimicamente , Glândulas Mamárias Animais/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Linhagem Celular , Feminino , Regulação da Expressão Gênica/fisiologia , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/genéticaRESUMO
Acute inflammatory response after photodynamic therapy is frequently described, and increase on mast cell degranulation is also present during this process. The mast cell activation may improve angiogenesis, and this fact has been associated with progression of oral premalignant lesions (OPL). The aim of this study was to evaluate whether photodynamic therapy (PDT) increases mast cell density (MCD) and microvessels density (MVD) in 4-nitroquinoline-1-oxide(4NQO)-induced OPL in rats. 4NQO-induced OPL were treated or not with 5-ALA followed by laser irradiation (PDT group and 4NQO groups, respectively). Mast cells and CD34+ microvessels were counted. Both PDT and 4NQO groups had MCD and MVD that were higher than normal mucosa (p b 0.05). The 4NQO group had the lowest number of non-degranulated MCD in comparison to experimental periods of PDT (PDT 6 h p=0.020; 24 h p=0.016; 48 h p=0.003; 72 h p=0.033). Only in the PDT group did MCD and MVD have a significant correlation (r= 0.6219, p = 0.010). 5-ALA-mediated PDT modified the MCD and MVD in the induced OPL, leading to degranulation of mast cells and angiogenesis. A PDT protocol with an efficient eradication of the OPL must be adopted considering the angiogenesis potential associated with the mast cell activation after the therapy.
Assuntos
Ácido Aminolevulínico/uso terapêutico , Mastócitos/fisiologia , Microvasos/patologia , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias da Língua/tratamento farmacológico , 4-Nitroquinolina-1-Óxido/toxicidade , Ácido Aminolevulínico/farmacologia , Animais , Antígenos CD34/metabolismo , Degranulação Celular/efeitos dos fármacos , Degranulação Celular/efeitos da radiação , Feminino , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Lasers , Mastócitos/citologia , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/efeitos da radiação , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Ratos , Ratos Wistar , Língua/patologia , Neoplasias da Língua/induzido quimicamente , Neoplasias da Língua/veterináriaAssuntos
Colite Ulcerativa/tratamento farmacológico , Esomeprazol/efeitos adversos , Mucosa Gástrica/patologia , Pólipos/patologia , Inibidores da Bomba de Prótons/efeitos adversos , Gastropatias/patologia , Criança , Colite Ulcerativa/complicações , Diagnóstico Diferencial , Feminino , Gastrite Hipertrófica/diagnóstico , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/diagnósticoRESUMO
CONTEXT: Zearalenone is a mycoestrogen and considered a mycotoxin. OBJECTIVE: To establish whether zearalenone produced hepatotoxicity via oral administration. METHODS: Zearalenone was orally administered at a dose of 50 mg, 100 mg and 200 mg ZEN/body weight/daily, respectively, for 14 days to three groups of BALB/c mice. Diagnostic modalities used to evaluate hepatic damage and impaired hepatic function pre- and post zearalenone administration included hepatic marker enzyme activity, pentobarbital sleeping time, cytochrome P-(450) activities and histopathologic evaluation of liver. RESULTS: Significant histopathologic changes viz. sinusoidal congestion, cytoplasmic vacuolization, hepatocellular necrosis and neutrophil infiltration were observed after evaluating of liver section from each group after accumulated zearalenone exposure. Further, zearalenone exposure increased activities of alanine transaminase, aspartate transaminase and lipid peroxides whereas activities of tissue glutathione and cytochrome P(450) were decreased as compared to control mice. Zearalenone also increased the sleeping time and decreased sleeping latency after pentobarbital through intraperitoneal route as compared to control mice which indicates that the impairment of hepatic metabolizing enzymes by zearalenone. CONCLUSION: Zearalenone is a potential hepatotoxin by oral route.
Assuntos
Fusarium/química , Fígado/patologia , Micotoxinas/toxicidade , Zearalenona/toxicidade , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Sistema Enzimático do Citocromo P-450/sangue , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Micotoxinas/administração & dosagem , Zearalenona/administração & dosagemRESUMO
CONTEXT: Zearalenone is a mycoestrogen and considered a mycotoxin. OBJECTIVE: To establish whether zearalenone produced hepatotoxicity via oral administration. METHODS: Zearalenone was orally administered at a dose of 50 mg, 100 mg and 200 mg ZEN/body weight/daily, respectively, for 14 days to three groups of BALB/c mice. Diagnostic modalities used to evaluate hepatic damage and impaired hepatic function pre- and post zearalenone administration included hepatic marker enzyme activity, pentobarbital sleeping time, cytochrome P-450 activities and histopathologic evaluation of liver. RESULTS: Significant histopathologic changes viz. sinusoidal congestion, cytoplasmic vacuolization, hepatocellular necrosis and neutrophil infiltration were observed after evaluating of liver section from each group after accumulated zearalenone exposure. Further, zearalenone exposure increased activities of alanine transaminase, aspartate transaminase and lipid peroxides whereas activities of tissue glutathione and cytochrome P450 were decreased as compared to control mice. Zearalenone also increased the sleeping time and decreased sleeping latency after pentobarbital through intraperitoneal route as compared to control mice which indicates that the impairment of hepatic metabolizing enzymes by zearalenone. CONCLUSION: Zearalenone is a potential hepatotoxin by oral route.
CONTEXTO: Zearalenone é um micoestrógeno e considerado como micotoxina. OBJETIVO: Avaliar se o Zearalenone produz hepatotoxicidade por administração via oral. MÉTODOS: Zearalenone foi administrada por via oral em doses de 50 µg, 100 µg e 200 µg/peso corporal/dia/14 dias, respectivamente, para três grupos de camundongos BAB/C. Modalidades diagnósticas usadas para avaliar o dano hepático e comprometimento da função hepática pré- e pós-administração de Zearalenone incluíram atividade enzimática de marcadores hepáticos, tempo de sono por pentobarbital, atividade do citocromo P-450 e avaliação histopatológica hepática. RESULTADOS: Alterações histopatológicas significantes como congestão sinusoidal, vacuolização citoplasmática, necrose hepatocelular e infiltração neutrofílica foram observadas após avaliação histológica de cada grupo após exposição acumulada de Zearalenone. Além disto, a exposição à Zearalenone incrementou a atividade das enzimas alanina transaminase e aspartato transaminase e peróxidos lipídicos, ao passo que as atividades teciduais de glutationa e citocromo P-450 diminuiram, quando comparadas com camundongos-controle. Zearalenone também aumentou o tempo de sono e diminuiu a latência do sono após a administração de pentobarbital por via intra-abdominal, quando comparados com camundongos-controle, o que indica o comprometimento das enzimas do metabolismo hepático por ela. CONCLUSÃO: Zearalenone é uma potente hepatotoxina quando administrada por via oral.
Assuntos
Animais , Camundongos , Fusarium/química , Fígado/patologia , Micotoxinas/toxicidade , Zearalenona/toxicidade , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , /sangue , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos Endogâmicos BALB C , Micotoxinas/administração & dosagem , Zearalenona/administração & dosagemRESUMO
Fipronil, active ingredient of the acaricide Frontiline®, is a phenyl-pyrazolic derivative, and its efficacy in the elimination of several plagues, even in low concentrations, has already been demonstrated; however, its effect on nontarget organisms has not been thoroughly explained. In this sense, the objective of this study was to evaluate the effects of different dosages of fipronil on the liver of mice in artificial conditions. Results showed that the animals exposed to fipronil present significant ultrastrucutural changes in hepatic cells with evident cellular and cytoplasm disorganization in hepatocytes characterized by an increase in the number of organelles, mainly mitochondria and rough endoplasmic reticulum, organelles that, in the case of the exposed animals, were probably responsible for the enzymes' synthesis that have the function of inactivating the toxic metabolites. A fat accumulation in the hepatocytes' cytoplasm (steatosis) was observed, in addition to extended vacuolated areas, mainly in regions next to the cell nucleus. Alterations observed in the nuclei of the hepatocytes pointed out cell death processes. Moreover, Kupffer cells increased in number (hyperplasia) suggesting an increase in the phagocytic activity of the liver in the exposed animals.
Assuntos
Hepatócitos/ultraestrutura , Fígado/efeitos dos fármacos , Pirazóis/toxicidade , Testes de Toxicidade , Acaricidas/toxicidade , Animais , Morte Celular , Núcleo Celular/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citoplasma/efeitos dos fármacos , Citoplasma/ultraestrutura , Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/induzido quimicamente , Feminino , Hepatócitos/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Células de Kupffer/efeitos dos fármacos , Células de Kupffer/ultraestrutura , Dose Letal Mediana , Fígado/citologia , Camundongos , Microscopia Eletrônica , Mitocôndrias/efeitos dos fármacos , Fagocitose , Pirazóis/administração & dosagemRESUMO
The aim of this study was to investigate oxidative DNA damage during 4-nitroquinoline 1-oxide (4NQO)-induced rat tongue carcinogenesis. For this purpose, male Wistar rats were distributed into three groups of 10 animals each and treated with 50 ppm 4NQO solution through their drinking water for 4, 12, and 20 weeks. Ten animals were used as negative control. The alkaline Comet assay modified with lesion-specific enzymes was used to detect single and double strand breaks, labile sites (SBs), and oxidised purines and pyrimidines. Although no histopathological abnormalities were induced in the epithelium after 4 weeks of carcinogen exposure, oxidative DNA damage was detected in the 'normal' oral epithelium. In pre-neoplastic lesions and squamous cell carcinomas induced after 12 and 20 weeks following carcinogen exposure, respectively, oxidative DNA damage was also increased (P < 0.05) when compared to negative control. In conclusion, our results suggest that oxidative DNA damage is an early event during multistep carcinogenesis assay induced by 4NQO. This kind of approach should be considered to persons with high risk of oral cancer, such as in smokers or alcohol consumers.
Assuntos
Carcinoma de Células Escamosas/induzido quimicamente , Dano ao DNA , Neoplasias da Língua/induzido quimicamente , 4-Nitroquinolina-1-Óxido , Animais , Carcinógenos , Carcinoma de Células Escamosas/patologia , Ensaio Cometa , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Masculino , Mucosa Bucal/efeitos dos fármacos , Mucosa Bucal/patologia , Oxirredução , Ratos , Ratos Wistar , Língua/efeitos dos fármacos , Língua/patologia , Neoplasias da Língua/patologiaRESUMO
Hypoxia events are common in many aquatic systems, which may be a natural event or provoked by anthropogenic actions, as well as accidents involving oil occurring throughout the world are frequent. Thus, through the possibility of occurrence of these two situations in same place the purpose of this study was to evaluate if damage caused by crude oil on genotoxic and morphological parameters in the marine fish species Hippocampus reidi will be aggravated by events of severe hypoxia. Sea horses were exposed during 8h to the following conditions: crude oil (OIL), severe hypoxia (HYP), association of severe hypoxia and crude oil (HYP+OIL) and normoxia without contaminant (CONT). An increase in micronuclei observed in OIL and HYP+OIL groups indicates that the crude oil exposure was a determining factor in the micronuclei induction and hypoxia did not intensify this result. In comet assays, both petroleum and hypoxia provoke DNA damage. The most frequent histopathology in the control groups and in those exposed to OIL and HYP+OIL groups were: hypertrophy and capillary dilation; hypertrophy and hyperplasia; hypertrophy, epithelial "lifting" and epithelial hyperplasia. An elongation of the lamellae was observed in fish from the two groups exposed to hypoxia, probably due to the fact that these groups required a greater flow of blood in the gills to increase the efficiency of gas exchange, since they were in a hypoxic environment. In summary, the micronuclei test and comet assay can be used as a good biomarker of contamination by petroleum. The association of hypoxia with crude oil in some aspects may exacerbate the responses of fish, in the light of the increase in DNA damage and the alterations in thickness of the gill epithelium.
Assuntos
Hipóxia/patologia , Mutagênicos/toxicidade , Oxigênio/análise , Petróleo/toxicidade , Água do Mar/análise , Smegmamorpha , Poluentes Químicos da Água/toxicidade , Animais , Biomarcadores/metabolismo , Capilares/efeitos dos fármacos , Capilares/patologia , Ensaio Cometa , Dano ao DNA , Epitélio/efeitos dos fármacos , Epitélio/patologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Brânquias/irrigação sanguínea , Brânquias/efeitos dos fármacos , Brânquias/patologia , Hiperplasia/induzido quimicamente , Hipertrofia/induzido quimicamente , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Petróleo/análise , Vasodilatação/efeitos dos fármacosRESUMO
We have previously demonstrated a crosstalk between fibroblast growth factor 2 (FGF2) and progestins inducing experimental breast cancer growth. The aim of the present study was to compare the effects of FGF2 and of medroxyprogesterone acetate (MPA) on the mouse mammary glands and to investigate whether the antiprogestin RU486 was able to reverse the MPA- or FGF2-induced effects on both, mammary gland and tumor growth. We demonstrate that FGF2 administered locally induced an intraductal hyperplasia that was not reverted by RU486, suggesting that FGF2-induced effects are progesterone receptor (PR)-independent. However, MPA-induced paraductal hyperplasia was reverted by RU486 and a partial agonistic effect was observed in RU486-treated glands. Using C4-HD tumors which only grow in the presence of MPA, we showed that FGF2 administered intratumorally was able to stimulate tumor growth as MPA. The histology of FGF2-treated tumors showed different degrees of gland differentiation. RU486 inhibited both, MPA or FGF2 induced tumor growth. However, only complete regression was observed in MPA-treated tumors. Our results support the hypothesis that stromal FGF2 activates PR inducing hormone independent tumor growth.
Assuntos
Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Antagonistas de Hormônios/farmacologia , Glândulas Mamárias Animais/efeitos dos fármacos , Neoplasias Mamárias Animais/tratamento farmacológico , Acetato de Medroxiprogesterona/antagonistas & inibidores , Mifepristona/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Hiperplasia/induzido quimicamente , Glândulas Mamárias Animais/patologia , Neoplasias Mamárias Animais/induzido quimicamente , CamundongosRESUMO
Disposal of tons of sludge produced daily by sewage treatment plants in large cities is a serious problem. Because recycling and application in agriculture have been proposed, the Brazilian National Environmental Council (CONAMA, 2006) issued a legal norm that regulates the use of the sewage sludge (SS) in crops. Due to the complex chemical nature of such products, characterization by analytical methods for health and environmental risk assessment has severe limitations. To overcome such limitations, it is necessary to (1) assess the toxicological potential of SS and (2) identify possible adverse effects in vivo in order to provide critical information for future environmental regulations. The present study was conducted to determine the potential toxicity of SS obtained from a representative urban treatment plant located in the Sao Paulo State, Brazil. Male and female Wistar rats were fed ad libitum a pelleted diet containing varying amounts of SS. No relevant clinical, hematological, urinary, or gross organ morphological alterations were observed in both genders of rats orally exposed to SS at up to 3.8 g/kg/d for 90 d. Sewage slude produced increased incidence of centrilobular hepatocyte hyperplasia at the high dose and significantly increased aspartate aminotransferease (AST) activities at all doses in both genders. Although the present data indicate some liver involvement, these alterations were considered adaptative and not toxicologically relevant, as the responses were relatively mild, not dose dependent, and no other parameters were markedly affected. The present results may contribute to the establishment of protocols for potential usage in SS agricultural soil application.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatócitos/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Esgotos/efeitos adversos , Animais , Brasil , Doença Hepática Induzida por Substâncias e Drogas/patologia , Feminino , Masculino , Ratos , Ratos Wistar , População UrbanaRESUMO
INTRODUCTION: Chronic allograft vasculopathy is an important cause of graft loss. Considering the inflammatory response in the development of chronic vascular lesions, therapeutic approaches to target the inflammatory process may be useful. We sought to investigate the possible protective effects on balloon catheter-induced vascular injury of thalidomide and tamoxifen, 2 drugs with powerful anti-inflammatory, immunomodulatory, and antifibrotic effects, using an animal model that mimics the morphologic features of chronic allograft vasculopathy. METHODS: Male Wistar rats subjected to balloon catheter carotid injury (INJ) were treated with thalidomide (100 mg/kg), or tamoxifen (10 mg/kg), or vehicle. Contralateral right carotid arteries were used as uninjured controls. Morphometric and immunohistochemical analyses were performed at 14 days postinjury. RESULTS: Injured carotid arteries showed marked neointimal hyperplasia, which was significantly inhibited among animals treated with thalidomide or tamoxifen: neointimal/media ratios of 1.4 +/- 0.4 versus 0.2 +/- 0.1 versus 0.4 +/- 0.2, for INJ, INJ + Thalid, and INJ + Tamox; respectively (P < .001). The endothelial cell loss was significantly less pronounced among animals subjected to carotid balloon injury that were treated with thalidomide (24 +/- 14 vs 1 +/- 1 cells per section in INJ, respectively (P < .05). Therapy with either thalidomide or tamoxifen effectively maintained alpha-smooth muscle actin expression in the media, similar to uninjured arteries. In this setting, tamoxifen was additionally effective to prevent the migration of myofibroblasts in to the intima. CONCLUSION: Thalidomide and tamoxifen were effective to reduce neointimal hyperplasia secondary to vascular damage. The vasculoprotective effects of thalidomide were more pronounced to preserve endothelial cells, whereas tamoxifen inhibited smooth muscle cell migration and proliferation. A possible beneficial effect of combined therapy with thalidomide plus tamoxifen should be addressed in future studies.
Assuntos
Artérias Carótidas/patologia , Lesões das Artérias Carótidas/prevenção & controle , Hiperplasia/prevenção & controle , Tamoxifeno/farmacologia , Talidomida/farmacologia , Túnica Íntima/patologia , Animais , Artérias Carótidas/efeitos dos fármacos , Hiperplasia/induzido quimicamente , Imuno-Histoquímica , Masculino , Ratos , Ratos Wistar , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/lesões , Túnica Média/efeitos dos fármacos , Túnica Média/lesões , Túnica Média/patologiaRESUMO
Vanadium, an important air pollutant derived from fuel product combustion, aggravates respiratory diseases and impairs cardiovascular function. In contrast, its effects on immune response are conflicting. The aim of our work was to determine if spleens of vanadium-exposed CD1 mice showed histological lesions that might result in immune response malfunction. One hundred and twelve CD-1 male mice were placed in an acrylic box and inhaled 0.02 M vanadium pentoxide (V2O5); actual concentration in chamber approximately 1.4 mg V2O5/m(3)) for 1 hr/d, twice a week, for 12 wk. Control mice inhaled only vehicle. Eight mice were sacrificed prior to the exposures. Eight control and eight V2O5-exposed mice were sacrificed 24 hr after the second exposure of each week until the 12-wk study was over. Another 8 mice that completed the 12-wk regimen were immunized with recombinant Hepatitis B surface antigen (HBsAg; three times over an 8-wk period) before sacrifice and analyses of their levels of anti-HBsAg antibody (HBSAb) using ELISA. In all studies, at sacrifice, blood samples were obtained by direct heart puncture and the spleen was removed, weighed and processed for H-E staining and quantitation of CD19 cells. The results indicated that the spleen weight of V2O5-exposed animals peaked at 9 wk (546 +/- 45 vs. 274 +/- 27 mg, p < 0.0001) and thereafter progressively decreased (321 +/- 39 mg at 12 wk, p < 0.001; control spleen = 298 +/- 35 mg). Spleens of V2O5-exposed animals showed an increased number of very large and non-clearly delimited germinal centers (that contained more lymphocytes and megakaryocytes) compared to those of control mice. In addition, their red pulp was poorly delimited and had an increase in CD19+ cells within hyperplasic germinal nodes. The mean HBsAb levels in immunized control mice were greater than that in the exposed hosts (i.e., OD = 0.39 +/- 0.03 vs. 0.11 +/- 0.05, p < 0.01). HBsAb avidity dropped to a value of 40 in V2O5-exposed animals vs. 86 in controls (p < 0.0001). We conclude that the chronic inhalation of V2O5, a frequent particle (PM(2.5)) component, induces histological changes and functional damage to the spleen, each of which appear to result in severe effects on the humoral immune response.
Assuntos
Poluentes Atmosféricos/toxicidade , Formação de Anticorpos/efeitos dos fármacos , Centro Germinativo/imunologia , Exposição por Inalação/efeitos adversos , Baço/imunologia , Compostos de Vanádio/toxicidade , Animais , Formação de Anticorpos/imunologia , Antígenos CD19/imunologia , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Centro Germinativo/patologia , Anticorpos Anti-Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/administração & dosagem , Hiperplasia/induzido quimicamente , Hiperplasia/imunologia , Hiperplasia/patologia , Imunização , Linfócitos/imunologia , Linfócitos/patologia , Masculino , Megacariócitos/imunologia , Megacariócitos/patologia , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/imunologia , Doenças Respiratórias/induzido quimicamente , Doenças Respiratórias/imunologia , Doenças Respiratórias/patologia , Baço/patologia , Fatores de TempoRESUMO
BACKGROUND: Testosterone (T) associated with estrogen (E) has been used in hormonal replacement therapy in postmenopause women and the effects of this hormonal association on the uterus are not known. OBJECTIVE: To study the effect of long-term simultaneous exposure to testosterone and estrogen on the uterus of non-castrated adult female rats. METHODS: Groups of ten adult noncastrated female Wistar rats were treated with non-esterified testosterone and beta estradiol (subcutaneous implants with 50 mg of each hormone) or with testosterone cipionate and estradiol valerate (weekly intramuscularly or by subcutaneous injection of respectively, 2.85 mg/kg and 0.166 mg/kg). Control groups received no treatment (10 rats) or injections of diluents (6 rats). All animals were killed six months after hormonal exposure. RESULTS: All rats treated with T+E developed hyperplasia and hyperkeratosis of the vaginal and cervical epithelium and focal metaplasia with keratinization of the endocervical and endometrial epithelium. Ascending pelvic inflammatory disease with pyometra and tuboovarian abscesses were frequent (25% mortality until the end of the experiment). CONCLUSIONS: Testosterone associated with estrogen induced metaplasia of the genital epithelium but did not induce neoplastic lesions. The metaplasic lesions reduced the mucosal defense mechanisms enhancing ascending genital inflammatory disease. Although metaplasia of the cervical and endometrial epithelium has been observed after estrogen exposure in rats, testosterone does not appear to inhibit these estrogen effects.
Assuntos
Estradiol/análogos & derivados , Estradiol/farmacologia , Hiperplasia/induzido quimicamente , Metaplasia/induzido quimicamente , Testosterona/farmacologia , Útero/efeitos dos fármacos , Animais , Colo do Útero/efeitos dos fármacos , Implantes de Medicamento , Interações Medicamentosas , Feminino , Injeções , Ratos , Ratos WistarRESUMO
OBJECTIVE: To evaluate the association of histologic changes in the breasts of female rats undergoing therapy with sex steroids. METHODS: An experimental study was conducted of 40 castrated female non-pubertal rats, 20 had given birth (Group B) and 20 had no offspring (Group A). After four weeks, these rats were randomly allocated to subgroups: A1, A2, A3, A4, A5 and B1, B2, B3, B4, B5. Steroids were given to subgroups as follows: A1 and B1--estradiol benzoate; A2 and B2--medroxyprogesterone acetate; A3 and B3--estradiol benzoate and medroxyprogesterone acetate; A4 and B4--tibolone; A5 and B5--placebo. After 10 weeks of treatment, animals were sacrificed and their mammary glands were analyzed. Histologic parameters evaluated were: epithelial cell proliferation, epithelial cells with secretory activity; and cell atypia in terminal duct units and buds or terminal alveoli. The association between microscopic analysis and diverse therapeutic regimens were analyzed by calculating the odds ratio and its respective 95% confidence interval. RESULTS: Histologic changes were observed in 29 rats: moderate hyperplasia (52.5%), hyperplastic alveolar nodule (42.5%), epithelial atypia (35%), mild hyperplasia (32.5%), secretory activity (20%) and severe hyperplasia (5%). In rats with no offspring when compared to the control, 1.3 times more hyperplastic alveolar nodules were found in the group treated with estradiol, the same was true for moderate hyperplasia in the rats that received medroxyprogesterone acetate, hyperplastic alveolar nodules and epithelial atypia in the group treated with estradiol plus medroxyprogesterone acetate. In the rats with offspring 1.3 times more secretory activity was found with estradiol. CONCLUSION: Epithelial hyperplasia and epithelial atypia with no proliferation are strongly associated to combined therapy with estradiol plus medroxyprogesterone acetate, mainly in the rats without offspring.